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A natural product is a chemical compound or substance produced by a living organism – found in nature. In the broadest sense, natural products include any substance produced by life. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients.
Within the field of organic chemistry, the definition of natural products is usually restricted to mean purified organic compounds isolated from natural sources that are produced by the pathways of primary or secondary metabolism. Within the field of medicinal chemistry, the definition is often further restricted to secondary metabolites. Secondary metabolites are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage. Many natural products are cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against, prey, predators, and competing organisms.
Natural products sometimes have pharmacological or biological activity that can be of therapeutic benefit in treating diseases. As such, natural products are the active components of many traditional medicines. Furthermore synthetic analogs of natural products with improved potency and safety can be prepared and therefore natural products are often used as starting points for drug discovery. In fact, natural products are the inspiration for approximately one half of U.S. Food and Drug Administration-approved drugs.
- 1 Classes
- 2 Natural sources
- 3 Medical uses
- 4 Isolation and purification
- 5 Synthesis
- 6 Research and teaching
- 7 Drugs
- 8 See also
- 9 References
- 10 Further reading
- 11 Journals
- 12 External links
The broadest definition of natural product is anything that is produced by a living organism and this would include organisms themselves. Based on this broad definition, natural products include:[undue weight? ]
- an entire organism (e.g., plant or animal or a microorganism)
- part of an organism (e.g., a leaf of a plant or an organ isolated from an animal)
- an extract from an organism
- a pure organic compound isolated from an extract
A more restrictive definition of a natural product is an "organic compound formed by living systems". The remainder of this article restricts itself to this more narrow definition.
Classification according to biological function
Organic natural products can be divided into the following three classes:
- Organic substances found in all cells and is essential to the survival of those cells and include amino acids, carbohydrates, lipids, and nucleic acids . These substances are known as primary metabolites.
- Polymeric organic materials such as cellulose, lignin, and proteins which form the structure of cells.
- Unique organic compounds that are found in a limited range of species. These are known as secondary metabolites.
Primary metabolites exert their actions on the organism that produces them. Secondary metabolites mainly exert their activity on other organisms through interaction with specific biological targets. Because of their ability to modulate biochemical and signal transduction pathways, some secondary metabolites have useful medicinal properties.
Natural products especially within the field of organic chemistry are often defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of medicinal chemistry and pharmacognosy.
Classification according to chemical structure
Types of secondary metabolites include (1) polyketides and fatty acids, (2) terpenoids (including steroids), (3) phenylpropanoids, (4) alkaloids, (5) specialized amino acids and peptides, and (6) specialized carbohydrates.
Natural products may be extracted from tissues of terrestrial plants, marine organisms or microorganism fermentation broths. A crude (untreated) extract from any one of these sources typically contains novel, structurally diverse chemical compounds, which the natural environment is a rich source of.
Chemical diversity in nature is based on biological and geographical diversity, so researchers travel around the world obtaining samples to analyze and evaluate in drug discovery screens or bioassays. This effort to search for natural products is known as bioprospecting.
Pharmacognosy provides the tools to identify, select and process natural products destined for medicinal use. Usually, the natural product compound has some form of biological activity and that compound is known as the active principle - such a structure can act as a lead compound (not to be confused with compounds containing the element lead). Many of today's medicines are obtained directly from a natural source.
On the other hand, some medicines are developed from a lead compound originally obtained from a natural source. This means the lead compound:
- can be produced by total synthesis, or
- can be a starting point (precursor) for a semisynthetic compound, or
- can act as a template for a structurally different total synthetic compound.
This is because many biologically active natural product compounds are secondary metabolites often with complex chemical structures. This has an advantage in that they are novel compounds but this complexity also makes many lead compounds' synthesis difficult and the compound usually has to be extracted from its natural source – a slow, expensive and inefficient process. As a result, there is usually an advantage in designing simpler analogues.
Plants have always been a rich source of lead compounds (e.g. Alkaloids, morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, and muscarine). Many of these lead compounds are useful drugs in themselves (e.g. Alkaloids, morphine and quinine), and others have been the basis for synthetic drugs (e.g. local anaesthetics developed from cocaine). Clinically useful drugs which have been recently isolated from plants include the anticancer agent paclitaxel (Taxol) from the yew tree, and the antimalarial agent artemisinin from Artemisia annua.
Plants provide a large bank of rich, complex and highly varied structures which are unlikely to be synthesized in laboratories. Furthermore, evolution has already carried out a screening process itself whereby plants are more likely to survive if they contain potent compounds which deter animals from eating them. Even today, the number of plants that have been extensively studied is relatively very few and the vast majority have not been studied at all.
Microorganisms such as bacteria and fungi have been invaluable for discovering drugs and lead compounds. These microorganisms produce a large variety of antimicrobial agents which have evolved to give their hosts an advantage over their competitors in the microbiological world.
The screening of microorganisms became highly popular after the discovery of penicillin. Soil and water samples were collected from all over the world in order to study new bacterial or fungal strains, leading to an impressive arsenal of antibacterial agents such as the cephalosporins, tetracyclines, aminoglycosides, rifamycins, and chloramphenicol.
Although most of the drugs derived from microorganisms are used in antibiotics, some microbial metabolites have provided lead compounds in other fields of medicine. For example, asperlicin - isolated from Aspergillus alliaceus - is a novel antagonist of a peptide hormone called cholecystokinin (CCK) which is involved in the control of appetite. CCK also acts as a neurotransmitter in the brain and is thought to be involved in panic attacks. Analogues of asperlicin may therefore have potential in treating anxiety. Other examples include the fungal metabolite lovastatin, which was the lead compound for a series of drugs that lower cholesterol levels, and another fungal metabolite called ciclosporin which is used to suppress the immune response after transplantation operations.
In recent years, there has been a great interest in finding lead compounds from marine sources. Coral, sponges, fish, and marine microorganisms have a wealth of biologically potent chemicals with interesting inflammatory, antiviral, and anticancer activity. For example, curacin A is obtained from a marine cyanobacterium and shows potent antitumor activity. Other antitumor agents derived from marine sources include eleutherobin, discodermolide, bryostatins, dolostatins, and cephalostatins.
Animals can sometimes be a source of new lead compounds. For example, a series of antibiotic peptides were extracted from the skin of the African clawed frog and a potent analgesic compound called epibatidine was obtained from the skin extracts of the Ecuadorian poison frog.
Venoms and toxins
Venoms and toxins from animals, plants, snakes, spiders, scorpions, insects, and microorganisms are extremely potent because they often have very specific interactions with a macromolecular target in the body. As a result, they have proved important tools in studying receptors, ion channels, and enzymes. Many of these toxins are polypeptides (e.g. α-bungarotoxin from cobras). However, non-peptide toxins such as tetrodotoxin from the puffer fish are also extremely potent.
Venoms and toxins have been used as lead compounds in the development of novel drugs. For example, teprotide, a peptide isolated from the venom of the Brazilian viper, was the lead compound for the development of the antihypertensive agents cilazapril and captopril.
The neurotoxins from Clostridium botulinum are responsible for serious food poisoning (botulism), but they have a clinical use as well. They can be injected into specific muscles (such as those controlling the eyelid) to prevent muscle spasm. These toxins prevent cholinergic transmission and could well prove a lead for the development of novel anticholinergic drugs.
Traditional medicine and ethnopharmacology
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In the past, indigenous peoples or ancient civilizations depended greatly on local flora and fauna for their survival.[better source needed] They would experiment with various berries, leaves, roots, animal parts or minerals to find out what effects they had. As a result, many crude drugs were observed by the local healer or shaman to have some medical use. Although some preparations may have been dangerous, or worked by a ceremonial or placebo effect, traditional healing systems usually had a substantial active pharmacopoeia, and in fact most western medicines up until the 1920s were developed this way. Some systems, like traditional Chinese medicine or Ayurveda were fully as sophisticated and as documented systems as western medicine, although they might use different paradigms. Many of these aqueous, ethanolic, distilled, condensed or dried extracts do indeed have a real and beneficial effect, and a study of ethnobotany can give clues as to which plants might be worth studying in more detail. Rhubarb root has been used as a purgative for many centuries. In China, it was called "The General" because of its "galloping charge" and was only used for one or two doses unless processed to reduce its purgative qualities. (Bulk laxatives would follow or be used on weaker patients according to the complex laxative protocols of the medical system.[page needed] The most significant chemicals in rhubarb root are anthraquinones, which were used as the lead compounds in the design of the laxative dantron. The extensive records of Chinese medicine about response to Artemisia preparations for malaria also provided the clue to the novel antimalarial drug artemisinin.
The therapeutic properties of the opium poppy (active principle morphine) were known in Ancient Egypt, were those of the Solanaceae plants in ancient Greece (active principles atropine and hyoscine). The snakeroot plant was well regarded in India (active principle reserpine), and herbalists in medieval England used extracts from the willow tree (salicin) and foxglove (active principle digitalis – a mixture of compounds such as digitoxin, digitonin, digitalin). The Aztec and Mayan cultures of Mesoamerica used extracts from a variety of bushes and trees including the ipecacuanha root (active principle emetine), coca bush (active principle cocaine), and cinchona bark (active principle quinine).
Insects have also gained recent attention as valuable sources of natural products and their use in traditional medicine has been reviewed.
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Isolation and purification
If the lead compound (or active principle) is present in a mixture of other compounds from a natural source, it has to be isolated and purified. The ease with which the active principle can be isolated and purified depends much on the structure, stability, and quantity of the compound. For example, Alexander Fleming recognized the antibiotic qualities of penicillin and its remarkable non-toxic nature to humans, but he disregarded it as a clinically useful drug because he was unable to purify it. He could isolate it in aqueous solution, but whenever he tried to remove the water, the drug was destroyed. It was not until the development of new experimental procedures such as freeze drying and chromatography that the successful isolation and purification of penicillin and other natural products became feasible.
A problem vis-a-vis the utility of isolation and purification to supply practical needs is that isolates often work differently than the original natural products which have synergies and may combine, say, antimicrobial compounds with compounds that stimulate various pathways of the immune system.[non-primary source needed]
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Not all natural products can be fully synthesized and many natural products have very complex structures that are too difficult and expensive to synthesize on an industrial scale. These include drugs such as penicillin, morphine, and paclitaxel (Taxol). Such compounds can only be harvested from their natural source – a process which can be tedious, time consuming, and expensive, as well as being wasteful on the natural resource. For example, one yew tree would have to be cut down to extract enough paclitaxel from its bark for a single dose. Furthermore, the number of structural analogues that can be obtained from harvesting is severely limited. Partial or semisynthetic procedures can sometimes get around these problems.
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Semisynthesis, or partial synthesis, involves harvesting a biosynthetic intermediate from a natural source, which is then converted to the final product by conventional procedures of chemical synthesis. This approach can have two advantages. First, the intermediate may be more easily extracted in higher yield than the final product itself. Second, it may allow the possibility of synthesizing analogues of the final product. The semisynthetic penicillins are an illustration of this approach. Another recent example is that of paclitaxel. It is manufactured by extracting 10-deacetylbaccatin III from the needles of the yew tree, then carrying out a four-stage synthesis.
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Research and teaching
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Research and teaching and teaching falls into a number of different academic areas, including pharmacognosy, ecology (e.g., chemical ecology), pharmacology (e.g., ethnopharmacology), and chemistry. Other biological areas include phylogenetics, comparative biochemistry and physiology, and modern systems biology; other areas in the physical sciences include cheminformatics.
Natural products chemistry is a distinct area of chemical research which was important in the history of chemistry, the sourcing of substances in early preclinical drug discovery research, the understanding of traditional medicine and ethnopharmacology, the evolution of technology associated with chemical separations, the development of modern methods in chemical structure determination by NMR and other techniques, and in identification of pharmacologically useful areas of chemical diversity space. In addition, natural products are prepared by organic synthesis, and have played an central role to the development of the field of organic chemistry by providing tremendously challenging targets and problems for synthetic strategy and tactics. In this regard, natural products play a central role in the training of new synthetic organic chemists, and are a principle motivation in the development of new variants of old chemical reactions (e.g., the Evans aldol reaction), as well as the discovery of completely new chemical reactions (e.g., the Woodward cis-hydroxylation, Sharpless epoxidation, and Suzuki–Miyaura cross-coupling reactions).
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A number of drugs have been derived from biological sources in nature, these include:
- Artemotil[page needed]
- Bleomycin[non-primary source needed]
- Codinaeopsin[non-primary source needed]
- Colchicine[non-primary source needed]
- Dimethyltryptamine[non-primary source needed]
- Ergotamine[page needed]
- Orlistat[non-primary source needed]
- Phenethylamine[better source needed]
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